tbuckley/cabot-search huggingface dataset:
Extracorporeal microchannel device to capture and eliminate circulating tumor cells from cancer patient’s blood.
Authors: Jayant Khandare, Alain D'Souza, Smriti Arora, Balram Singh, Gourishankar Aland, Narendra Kale, Isha Gore, Arnav Deshmukh, Rick Kamble, Vikas Jadhav, Pankaj Chaturvedi
Journal: Journal of Clinical Oncology (2022)

e14522 Background: Metastatic progression accounts for nearly 90% of cancer-related deaths and has been directly correlated with the presence of circulating tumor cells (CTCs) in numerous carcinomas including breast, lung, ovarian, colorectal, and head and neck cancers. The removal of CTCs from cancer patient’s blood is directly implicated with reduction of extravasation and disease invasiveness to secondary organs. Methods: We designed and printed 3 Dimensional (3D) microchannel devices using biocompatible polymer and packed it with anti-EpCAM (EpCAM) mediated glass-based (G) compositions (G-EpCAM). The computational fluid dynamic (CFD) analysis simulation was explored to optimize the hemodynamic effect of the G-EpCAM device for measuring the pressure and velocity difference for blood along the spiral flow microchannels. Red blood cell (RBC) hemolysis was estimated using G-EpCAM compositions packed in a device to determine optimal biocompatibility. We assessed cancer cell lines (breast cancer MCF7, lung cancer A549) interactions and capture with varying incubation time points, effect of anti-EpCAM concentrations, number of G-EpCAMs, and series of devices. We evaluated G-EpCAM-on-device’s CTC capture capability and biocompatibility using head and neck, colorectal, lung, and ductal breast cancer patient’s blood samples. All G-EpCAM captured CTCs were immuno-stained for cytokeratin 18 (CK18) expression and the optimal fluorescence acquisition intensity was quantified. Results: Extracorporeal G-EpCAM microchannel device was 3D printed and consisted of interlocking top lid and bottom base with inlet and outlet channels. The path length of the spiral device consisted of 20 microchannels with 6.0-feet length. Device accommodated 28 gm of non-hemolytic G-EpCAM compositions. CFD analysis showed 3.8 mm as the ideal channel diameter and 2mm as the superlative G-EpCAM diameter for maximal cells and CTC capture with minimal blood hemolysis (less than 1%) as compared to control. Series 1 and 2 device indicated 90% and 85% cell capture efficiency, respectively using G-EpCAM devices indicating highest interactions and efficiency with cells. Conversely, the first device in series captured the highest cells. In addition, the efficiency improved as the number of G-EpCAM compositions was increased. We accounted device to capture CTCs with specificity having G-EpCAM composition and observed no hemolysis and non-specific interactions with other blood cells like RBCs or leukocytes. Conclusions: Continuous CTC removal from cancer patient’s blood circulation using such device offers promising therapeutic utility in stemming aggressive metastatic invasion and progression for improving the overall survival of epithelial origin cancer patients. Clinical trial information: CTRI U1111/1192-3951.
Reducing post-operative emergency department visits and readmissions after nephrectomy: An initial evaluation of the MUSIC-KIDNEY registry
Authors: M. Butaney, A. Johnson, A. Bulusu, D. Gandham, J. Qi, M. Jamil, A. Patel, S. Noyes, J. Anema, M. Levin, B. Rosenberg, B.R. Lane, C.G. Rogers
Journal: European Urology (2022)
MEDB-10. Comparing pediatric medulloblastoma with and without spinal metastasis
Authors: Phua Hwee Tang, Sameema Nisa
Journal: Neuro-Oncology (2022)

Abstract AIM: To compare pediatric medulloblastoma with and without spinal metastasis METHODOLOGY: Pediatric medulloblastoma cases from 1999 to 2021 were retrospectively reviewed in this Institutional Review Board approved study. Imaging reports, presence of spinal drop metastases at diagnosis, degree of tumor excision, treatment given and survival status were captured. RESULTS: Brain and spine imaging at diagnosis was available in 54 medulloblastoma patients with no drop metastasis and in 7 with drop metastasis. Largest tumor dimension at presentation is 4.54 ± 0.94 cm with those with drop metastasis, similar to the 4.43 ± 0.94 cm in those without drop metastasis (p = 0.79). For the 54 medulloblastomas with no drop metastasis, 44 (81%) were completely excised, 9 (17%) partially excised and there was no follow up for 1. For the 7 medulloblastomas with drop metastasis, 3 (43%) of the primary tumours were completely excised, 3 (43%) partially excised and there was no follow up for 1. Post operative chemo/radiotherapy was given to 48 of the 54 with no drop metastasis, not given for 1 with no information available for 5. Chemo/radiotherapy was given to 6 of the 7 with drop metastasis with no information available for 1. At 1 year follow up of the 54 with no spinal drop metastasis at diagnosis , 42 remain tumour free, 3 have tumour, 4 are deceased and 5 are lost to follow up. At 1 year follow up of the 7 with drop metastasis, 2 are free of tumour, 2 have tumour and 3 are lost to follow up. Higher percentage of medulloblastomas without drop metastasis are completely excised (p&amp;lt;0.01). No significant difference between postoperative chemotherapy/radiation rates between groups CONCLUSION: Most medulloblastomas do not have spinal drop metastasis at diagnosis and complete excision is more frequently in those without drop metastasis.
Progression patterns by types of metastatic spread, prostate-specific antigen (PSA), and clinical symptoms: Post-hoc analyses of ARAMIS.
Authors: Alicia K. Morgans, Christopher Sweeney, Christopher J.D. Wallis, Susan Halabi, Andrew J. Armstrong, Frank Verholen, Jorge A. Ortiz, Anja Schmall, Shankar Srinivasan, Marc-Oliver Grimm
Journal: Journal of Clinical Oncology (2022)

5044 Background: Darolutamide (DARO), a highly potent and structurally distinct androgen receptor inhibitor, prolonged metastasis-free survival by nearly 2 years and reduced the risk of death by 31% vs placebo (PBO) with a favorable tolerability profile in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC) in ARAMIS. We present post-hoc analyses of ARAMIS to evaluate the association between metastatic progression with prostate-specific antigen (PSA) and clinical progression and to describe the distribution of metastatic progression between groups. Methods: Pts with nmCRPC were randomized 2:1 to DARO (n=955) or PBO (n=554) while continuing androgen-deprivation therapy. Descriptive analyses were performed using the primary data cutoff (Sept 3, 2018) for the double-blind period. Post-baseline metastases were based on central review of conventional radiographic imaging every 16 weeks. PSA and pain progression were defined per primary analysis ( N Engl J Med. 2019;380:1235-46). Results: Metastatic progression was observed in 13.6% of DARO and 28.5% of PBO pts. Most pts had isolated progression as bone (DARO 46%, PBO 39%) or lymph node (32%; 40%) metastasis (Table). Pts with radiographic progression had shorter median time from initial diagnosis to study treatment (DARO 72.9, PBO 74.4 months) vs the overall ARAMIS population (86.2, 84.2 months). Of all pts with metastatic progression, baseline PSA levels (ng/mL) were similar in DARO (12.6) and PBO pts (15.1); DARO pts had lower median PSA before metastasis (16.7) vs PBO pts (48.0) and median absolute/relative PSA decrease from baseline of -0.7/-3.2% vs an increase for PBO pts of 29.5/181%. PSA progression before metastasis was observed in 55.6% (160/288) of pts, occurring in fewer DARO (45.4%) vs PBO pts (63.9%) (treatment difference 18.5%; nominal 95% CI 6.5%–30.6%). The median time between PSA progression and metastasis was 7.0 months with DARO vs 5.6 months with PBO. Pain progression before metastatic progression was rare and similar between groups (DARO 16.9%, PBO 17.7%). Conclusions: DARO significantly reduced risk of metastatic progression and improved overall survival vs PBO without changing the pattern of metastatic progression. Many pts with nmCRPC experienced metastatic progression without PSA progression, and pain progression was rare. These results support the use of imaging with PSA monitoring to properly identify disease progression in pts with nmCRPC. Clinical trial information: TBC. [Table: see text]
PSA doubling time as predictor of relapse after early salvage radiation therapy: When should imaging be used to select patients who might not benefit from early local treatments?
Authors: N. Fossati, J.R. Karnes, S.A. Boorjan, A. Bossi, N. Di Muzio, C. Cozzarini, B. Noris Chiorda, G. Gandaglia, E. Mazzone, A. Stabile, D. Bartkowiak, S. Shariat, G. Goldner, S. Joniau, C. Berghen, G. De Meerleer, H. Van Poppel, A. Gallina, F. Montorsi, T. Wiegel, A. Briganti
Journal: European Urology (2022)
Bladder NIRS: A non-invasive method functional to distinguish between detrusor underactivity (DU) and Bladder Outlet Obstruction (BOO) in men with LUTS
Authors: L. Romei, P. Tuzzolo, A. Civitella, F. Prata, V. Crimi, F. Esperto, R. Prof. Papalia, R.M. Prof. Scarpa
Journal: European Urology (2022)
Promising efficacy of immune-checkpoint inhibitor with chemotherapy for SMARCA4-deficient thoracic sarcomatoid tumors.
Authors: Ying Lin, Yao Zhang, Zhihuang Hu, Xianghua Wu, Jialei Wang, Huijie Wang
Journal: Journal of Clinical Oncology (2022)

e21074 Background: SMARCA4-deficient thoracic sarcomatoid tumors (SD-TSTs) is a rare and highly aggressive disease that lack clear treatment guidelines. This research reports the clinicopathological features of SD-TSTs and the promising efficacy of immune-checkpoint inhibitor with chemotherapy in SD-TSTs. Methods: A total of 16 patients were diagnosed and treated with SD-TSTs in Fudan University Shanghai Cancer Center (FUSCC) from January, 2017 to December, 2021. Clinicopathologic, genomic characteristics and treatment information were obtained and analyzed. Results: SD-TSTs were diagnosed at median age of 64.5 years old, and predominantly affected male (100%) with heavier smoking history (≥20 pack-year). Many patients were diagnosed at advanced stages (Stage I 18.8%, Stage II 25%, Stage III 25% and Stage IV 43.8%). The most often metastatic sites were adrenal gland, lymph nodes, bone and liver, while brain metastasis was not found. For patients underwent radical therapy, median disease-free survival is 4.8 months, indicating a rapid relapse pattern even for early-stage patients. 8 patients with Stage IV SD-TSTs were treated in FUSCC. As for first-line therapy, 3 patients received chemotherapy, whose regimen included gemcitabine plus cisplatin, doxorubicin plus ifosfamide, and vincristine, doxorubicin plus cyclophosphamide alternating with ifosfamine and etoposide. 5 patients received immune-checkpoint inhibitor plus chemotherapy as first-line therapy, including 3 patients treated with pembrolizumab plus nab-paclitaxel and carboplatin, 1 patient treated with tislelizumab plus nab-paclitaxel and carboplatin and 1 patient treated with sintilimab plus paclitaxel and carboplatin. Median progression-free survival (PFS) of first line was 6.53 months for all patients. First-line median PFS was significantly higher for patients with immune-checkpoint inhibitor plus chemotherapy than those treated with only chemotherapy (not reach vs. 2.73 months, p = 0.07). This result suggested that SD-TSTs were irresponsive to chemotherapy, including those used for sarcomas, and better responded to immune-checkpoint inhibitor included regimen. Conclusions: SD-TSTs is a highly aggressive disease. Immune-checkpoint inhibitor combined with chemotherapy showed promising efficacy in metastatic SD-TSTs than traditional chemotherapy. Considering the low incidence of SD-TSTs, our research contains the largest sample size by far to report the efficacy of immune-checkpoint inhibitor plus chemotherapy in this deadly disease.
A phase Ia/Ib study evaluating the safety and efficacy of intratumorally administrated OH2, an oncolytic herpes simplex virus 2, in unresected stage IIIC to IV melanoma patients.
Authors: Xuan Wang, Chuanliang Cui, Bin Lian, Lu Si, Zhihong Chi, Xinan Sheng, Yan Kong, Han Hu, Xiangyong Gu, Caili Li, Lili Mao, Xue Bai, Bixia Tang, Xieqiao Yan, Siming Li, Li Zhou, Binlei Liu, Jun Guo
Journal: Journal of Clinical Oncology (2022)

e21537 Background: OH2 is a herpes simplex virus type 2-derived oncolytic virus. It was engineered to selectively replicate within tumors and express granulocyte macrophage colony-stimulating factor (GM-CSF) to enhance tumor-specific immune responses. We conducted a phase Ia/Ib clinical trial to evaluate the safety and preliminary efficacy in unresected stage IIIC to IV melanoma patients (pts). Methods: In this phase Ia/Ib trial, we enrolled pts aged between 18-75 with histologically confirmed unresectable stage III or distant metastatic melanoma failed with prior therapies. In phase Ia, nine pts were in the single-dose group, where 3 dose levels (10 6 , 10 7 , and 10 8 CCID50/mL) of OH2 were assessed. And six pts were in the multi-dose group testing multiple administration regimens. The recommended doses were then expanded in phase Ib. The primary objective was the safety and tolerability of OH2 injection as defined by the dose-limiting toxicities (DLTs) and the maximum-tolerated dose (MTD) in phase Ia. Antitumor activity was assessed per Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) and immune-RECIST in phase Ib. The clinical trial information: NCT04386967. Results: 35 pts were enrolled between November, 2018 and December, 2021. Among this, 37.1% were stageIVM1b-M1c; 88.6% had received of previous treatments: In the phase Ia study, OH2 was well-tolerated, neither serious AEs (SAEs) nor death were reported. No patient experienced TEAE leading to early withdrawal. Most TRAEs were Grade 1 in severity. There were no Grade 3 or above TRAEs. No DLTs were recorded, and the most frequent TRAEs were pyrexia (80%), Skin depigmentation (26.7), Oedema peripheral (26.7%), which were similar in three different doses of the single-dose group. The one-year survival rate was 93.3 % with median overall survival (mOS) being 20.8 months (still ongoing). In the phase Ib study, five pts achieved immune-partial response/partial response. The overall response rate (ORR) was 25.0 % and the five pts had ongoing responses. Six pts experienced stable disease (SD) with a disease control rate (DCR) being 55 %. The durable response rate (partial or complete response for ≥ 6 months) was 60 %. There were seven III-IV1a pts prior treated with anti-PD-1 antibodies. Three of the seven pts achieved iPR/PR (42.9 %), with DCR being 85.7 %. Conclusions: OH2 oncolytic virotherapy showed a favorable safety profile with no DLTs. And exhibited durable antitumor activity in pts. It warrants further investigation for the treatment of pts with unresectable melanoma. Clinical trial information: NCT04386967.
Health Related Quality of Life (HRQOL) four years after radical cystectomy – does the type of urinary diversion matter?
Authors: Y. Volz, L. Eismann, P.E. Paulo, T. Westhofen, B.E. Ebner, J-F. Jokisch, G.B. Schulz, B.S. Schlenker, A.K. Karl, C.G. Stief, A. Kretschmer
Journal: European Urology (2022)
Menin inhibitors as targeted therapeutics in KMT2a rearranged infant leukemia and the identification of effective treatment combinations.
Authors: Ritul Sharma, Chunfen Zhang, Luke Devon Maese, Norman James Lacayo, Aru Narendran
Journal: Journal of Clinical Oncology (2022)

10024 Background: KMT2a rearrangements are a hallmark of infant (less than 1 year of age) leukemia and are associated with poor prognosis. Menin is a ubiquitous protein that binds to the N-terminal of the KMT2a-fusion protein to mediate the oncogenic activity of KMT2a-rearranged leukemia cells. In this study, we evaluated the effect of multiple menin inhibitors and effective drug combinations for the treatment of KMT2A-rearranged infant leukemia. Methods: FISH analysis and immunoblotting confirmed the presence of KMT2a-fusion in the primary patient samples and cell lines studied. Lymphocytes from healthy donors were used as controls. Cells were treated with various concentration of multiple menin inhibitors for 72 hours and growth inhibition was measured using alamar blue assay. Infant leukemia cells were treated with a panel of FDA-approved agents (n = 221) to identify potential synergy, additive- and antagonistic-effects with specific menin inhibitors. Therapeutic drug interaction properties were established by calculating combination indices (CI) using the Chou-Talalay method. Mode of cell death and cellular target modulations were determined by western blot analysis. The effect of targeting menin in the context of the leukemogenic bone marrow microenvironment was determined through stromal cell co-cultures. Results: A comprehensive analysis of menin inhibitors on infant leukemia cell lines and primary patient cells exhibited significant and quantitatively diverse responses in cells with distinct molecular properties. Within the panel of menin inhibitors, infant B-ALL cells were found to be more sensitive to MI-463, MI-503 and MI-136 with a mean IC 50 of 5.9µM, 6.1µM and 10.2µM, respectively. On the other hand, MI-3 exhibited an IC 50 of 35.6µM. The cytotoxic effect of menin inhibitors on normal lymphocytes was minimal, suggesting a favourable therapeutic window (p &lt; 0.0001). High-throughput screening with a library of &gt; 200 FDA-approved drugs revealed significant sensitivity of distinct infant leukemia cells to proteasome, HDAC and CDK9 inhibitors. Among these, substantial drug synergy was observed between menin and proteasome inhibitors. For example, carfilzomib synergised with menin inhibitors over a broad range of concentrations with a CI value of 0.7. Conclusions: In this study, we present and discuss the initial proof-of-concept preclinical data for the effective anti-leukemic activity of menin inhibition against KMT2A-rearranged infant leukemia cells. Furthermore, the comprehensive drug screen and drug combination studies identified a spectrum of mechanistically-validated synergies, providing usable data for the formulation of multi-agent clinical studies for this currently unmet need in pediatric oncology.
HGG-48. A comparative proteomic analysis of the cell membrane of histone 3 mutated paediatric high-grade gliomas in order to identify potential immunotherapeutic targets
Authors: Sneha Suresh, Alina Khan, Anya Snary, James Pickering, Ruman Rahman, Richard Grundy, Robert Layfield, Farhana Haque
Journal: Neuro-Oncology (2022)

Abstract Improvements in the treatments for childhood and adolescent brain tumours, High-Grade Glioma (pHGG) and Diffuse Intrinsic Pontine Glioblastoma (DIPG), have not advanced much and they continue to carry a very poor prognosis. These brain tumours are now defined by mutations affecting histone 3 proteins, indeed 80% of DIPGs harbour histone H3.1 and H3.3 K27M somatic mutations whilst 30% of pHGGs exhibit H3.3 G34R or G34V mutations. We hypothesized that the histone 3 mutant tumours will have distinct mutation specific surfactome or cell surface proteins. We therefore analysed the cell surface proteomics of H3.3 G34V and G34R mutated high-grade glioma in comparison to the H3 wild-type Glioma, to explore whether these proteins have the potential to be used as immunotherapeutic targets. We have at first isolated the cell membrane fractions from a range of patient cells carrying histone 3 mutations (G34R, G34V) relative to wild type histone 3. A comparative quantitative liquid chromatographic mass-spectrometry analyses of these cell surface membrane fractions were performed to identify specific targetable factors. The results of these were analysed with the focus in identifying proteins that can be targeted for tumour specific immune modulation or immunotherapeutic intervention. Results of these analyses will be presented.
Clinical validation of a multicancer detection blood test by circulating cell-free DNA (cfDNA) methylation sequencing: The THUNDER study.
Authors: Qiang Gao, Yuzi Zhang, Jiayue Xu, Guoqiang Wang, Jing Zhao, Xiaofang Wen, Bingsi Li, Zhihong Zhang, Shangli Cai, Jia Fan, Jing Su
Journal: Journal of Clinical Oncology (2022)

10544 Background: The development of ultra-sensitive genomic and epigenomic assays enables the early detection of multiple cancers in parallel. However, large-scale prospective clinical validation data are rare. Here, we report clinical validation data from the THUNDER (The Unintrusive Detection of EaRly-stage cancers, NCT04820868) study, which evaluates the performance of ELSA-seq among 6 cancer types in lung, colorectum, liver, esophagus, pancreas and ovary, which account for 50% of cancer morbidity and 62% of cancer mortality. Methods: This prospective case-control study consists of four stages: marker discovery, model training, validation, and independent validation. A customized panel covering 161,984 CpG sites was established using public data and in-house data. Cancer patients were pre-specified into the training and validation sets, and healthy controls (HC) were age-matched. Two multi-cancer detection blood test (MCDBT-1 and MCDBT-2) models with different cut-offs were established from the retrospectively collected training set and tested in the validation set. An independent validation set was enrolled prospectively, matched by age, and tested with the locked MCDBT-1/2 models. An interception model was then applied based on the model performance and China cancer incidence data to infer potential positive predictive value (PPV) and clinical utility in real-world practice. Results: In total, the training set consisted of 399 cases and 626 HC; the validation set consisted of 301 cases and 123 HC; and the independent validation set consisted of 505 cases and 505 HC. In the training set, the specificities were 98.9% (95% confidence interval [CI], 97.7%‒99.5%) and 99.7% (98.8%‒100.0%) for MCDBT-1/2 models, respectively. In the independent validation set ( n = 856, the rest to be sequenced and reported), MCDBT-1 and MCDBT-2 yielded sensitivity of 76.2% (72.0%‒80.0%) and 70.2% (65.8%‒74.4%) in 6 cancers with specificity of 96.3% (93.9%‒97.9%) and 99.3% (97.8%‒99.8%), respectively. Stage I‒III sensitivity was 68.5% (63.1%‒73.5%) and 60.8% (55.3%‒66.2%) for MCDBT-1/2 models, respectively. The prediction accuracy of top predicted origin was 79.1% (74.5%‒83.2%) and 83.0% (78.4%‒87.0%) for MCDBT-1/2, respectively. The interception model projected an estimated PPV of 3.1% and 12.4% for MCDBT-1/2 models, respectively. MCDBT-1 could reduce 5-year cancer mortality by 20.3%‒24.6% and reduce late-stage incidence by 51.7%‒61.7%, and MCDBT-2 could reduce 5-year cancer mortality by 15.9%‒19.9% and reduce late-stage incidence by 40.9%‒49.2%. Conclusions: cfDNA methylation-based MCDBT-1/2 models can effectively identify multiple cancers simultaneously at early stages with promising sensitivity, specificity, and accuracy of predicted origin. Their performances are to be further validated in a prospective interventional study (NCT05227534).